Heart disease remains one of the leading causes of death. The high incidence of heart disease has led to the identification of various risk factors that may be controlled in an effort to reduce such disease. One risk factor is hypercholesterolemia, which is a condition of high blood levels of cholesterol. Cholesterol is a fatty substance that is made by the liver, and also is present in many foods. Cholesterol circulates in the blood associated with several forms of lipoproteins. Some of these forms are now referred to as "good" forms of cholesterol, while others are "bad". For example, one such lipoprotein with which cholesterol associates is referred to as low-density lipoprotein or LDL. LDL-cholesterol (LCL-C) is the form in which cholesterol leaves the liver destined for cells throughout the body. High levels of LDL-C are bad, because they have been shown to cause rapid clogging of coronary arteries with fatty deposits, resulting in the disease known as atherosclerosis, which often leads to heart attacks. A great deal of effort is currently underway to get people to reduce their levels of LDL-C, for example, by modifying diet and exercise.
In contrast, a good form of cholesterol is that associated with high-density lipoprotein, i.e., HDL-cholesterol (HDL-C). This is the form in which cholesterol is pulled out of cells and goes back to the liver for disposal.
A modified form of LDL is known as lipoprotein(a), "Lp(a)". It consists of LDL covalently linked through a disulfide bond to apolipoprotein(a), "apo(a)" Lp(a) cholesterol appears to be a bad form of cholesterol, since elevated levels of Lp(a) have been associated with the development of a variety of vascular diseases including atherosclerosis, coronary heart disease, angina, myocardial infarction, cerebral infarction, ischemic stroke, and restenosis following balloon angioplasty. In fact, Lp(a) appears to be an excellent predictor for stroke. Accordingly, high concentrations of Lp(a) is one of the major risk factors leading to death from heart disease.
We have now discovered that isothiazolones are effective in lowering plasma concentrations of Lp(a). This invention thus provides a method for lowering plasma levels of Lp(a) comprising administering a isothiazolone.
Certain isothiazolones are known which have various pharmaceutical utilities, most notably antimicrobial activity. Okachi, et al., J. Med. Chem., 1985;28:1772-1779, describe several 1,2-benzisothiazolones which have marginal antibiotic activity and which were primarily utilized as intermediates in the synthesis of 2,2'-dithiobis (benzamide) derivatives. Carmellino, et al., Eur. J. Med. Chem., 1994;29:743-751, disclose a variety of 1,2-benzisothiazolones as antibacterial and antifungal agents. Miller, et al., U.S. Pat. No. 3,517,022, disclose 2-carbamoyl-1, 2-benzisothiazolones which are said to be active against bacteria, fungi, and algae. Morley, in U.S. Pat. No. 3,012,039, describes 2-alkyl-1,2-benzisothiazolones which are useful as antibacterials and antifungals. Sherba, et al., U.S. Pat. 5,219,875, describe synergistic antimicrobial compositions 5 comprising 2-unsubstituted 1,2-benziso-thiazolin-3-one and iodopropargyl butylcarbamate. Laber, et al., U.S. Pat. No. 4,049,817, describe synergistic antimicrobial compositions containing a variety of 2-substituted and 2-unsubstituted benzisothiazolinones.
Grivos, U.S. Pat. No. 3,761,489, describes a series of substituted N-alkyl benzisothiazolinones which are said to be active against bacteria, fungi, and yeasts. Grivos, U.S. Pat. No. 3,661,974, describes the synthesis of various 2-substituted 1,2-benzisothiazolin-3-ones from 2-carbalkoxy-phenyl sulfonamides. The thiazolinones are said to be useful as antibacterials and antiseptics.
There have been no reports that isothiazolones effect plasma levels of Lp(a). We have now discovered that plasma Lp(a) can be lowered by administering an isothiazolone, and accordingly an object of this invention is to provide a method for lowering Lp(a), and thereby treating and preventing coronary artery disease.